title: Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice.
abstract: Exposure to sodium valproate (VPA) in utero increases the risk of language impairment and a diagnosis of autism spectrum disorder (ASD). Mice exposed to VPA while in utero have also shown postnatal social deficits. Inhibition of histone deacetylase (HDAC) is one of VPA's many biological effects. The main objective of this study was to test the hypothesis that HDAC inhibition causes these behavioral outcomes following prenatal VPA exposure in mice. We exposed embryonic mice to VPA, the HDAC inhibitor trichostatin A (TSA), or vehicle controls. TSA (1mg/kg) inhibited HDAC in embryonic tissue at a level comparable to 600 mg/kg VPA, resulting in significant increases in histone H3 and H4 acetylation, and histone H3 lysine 4 tri-methylation. Postnatally, decreases in ultrasonic vocalization, olfactory motivation and sociability were observed in TSA and VPA-exposed pups. Treated mice exhibited elevated digging and grooming suggestive of mild restrictive and repetitive behaviors. Olfactory social preference, social novelty and habituation were normal. Together, these data indicate that embryonic HDAC inhibition alone can cause abnormal social behaviors in mice. This result serves as a molecular understanding of infant outcomes following mild VPA exposure in utero.
authors.affiliation: The University of Queensland, Centre for Advanced Imaging, Brisbane, Australia. Electronic address: r.moldrich@uq.edu.au.
authors.forename: Randal X
authors.initials: RX
authors.lastname: Moldrich
authors.forename: Gayeshika
authors.initials: G
authors.lastname: Leanage
authors.forename: David
authors.initials: D
authors.lastname: She
authors.forename: Elliot
authors.initials: E
authors.lastname: Dolan-Evans
authors.forename: Michael
authors.initials: M
authors.lastname: Nelson
authors.forename: Nargis
authors.initials: N
authors.lastname: Reza
authors.forename: David C
authors.initials: DC
authors.lastname: Reutens
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004622:Embryo, Mammalian; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007398:Interpersonal Relations; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000503:physiopathology*; D045442:Rotarod Performance Test; D012903:Smell / Q000187:drug effects; D012920:Social Behavior Disorders / Q000209:etiology*; D014635:Valproic Acid / Q000008:administration & dosage*; D014828:Vocalization, Animal / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D014635:Valproic Acid; D006655:Histone Deacetylases
keywords: Autism; Histone acetylation; Histone deacetylase; Sociability; Sodium valproate; Trichostatin A